Interleukin-1a Blockade Reduce Acute Myocardial Ischemic Injury In The Mouse

Abstract

Introduction: The inflammatory response during acute myocardial infarction (AMI) amplifies myocardial tissue injury and promotes adverse remodeling and heart failure. We sought to investigate the molecular signaling for the initial response during AMI. Hypothesis: The release of Interleukin-1α (IL-1α) by dying cells during AMI leads to pro-inflammatory signaling and activation of caspase-1 in the heart, leading to further increase in infarct size. Methods: Adult male CD1 mice underwent ligation of the left anterior descending coronary artery to induce a transient myocardial ischemia for 30 minutes, followed by 24 hours of reperfusion. The R&D systems polyclonal IL-1α blocking antibody (15 μg/Kg) or vehicle were injected intraperitoneally at the onset of the reperfusion (N=6-8 per group). Transthoracic echocardiography was performed to measure left ventricular fractional shortening (LVFS) prior to sacrifice. We used a fluorogenic assay for caspase-1 activity in the heart and triphenyl tetrazolium chloride (TTC-staining) to measure infarct size at 24 hours. Invitro experiments on cells viability were conducted HL-1 (mouse atrial cardiomyocyte tumor lineage). HL-1 were primed for 4 hours with exogenous IL-1α (100 ng/ml), followed by 30 min of ATP (5mM) stimulation. In simulated hypoxic conditions for 6h HL-1 cells were incubated whit IL-1α-AB (50ng/ml). Results: IL-1α blockade with a blocking antibody after ischemia significantly reduced caspase-1 activity in the heart, associated with a significant reduction in infarct size, and preservation in LVFS at 24 hours. Addition of IL-1α to the culture medium of HL-1 cells significantly increase cell. Invitro IL-1α-blockade significantly reduced cells death after 6 hour of simulated hypoxia. Conclusion: IL-1α release during AMI leads to amplification of the inflammatory response and exacerbation of myocardial injury due to activation of the caspase-1 during AMI. IL-1α blockade may represent a viable therapeutic strategy as an adjunct to reperfusion in patients with AMI.